Parenterals product requiring sterile packaging: Production procedure (Part – I) and MCQs for GPAT, NIPER, Pharmacist and Drug Inspector exam

Parenterals product requiring sterile packaging: Production procedure (Part – I) and MCQs for GPAT, NIPER, Pharmacist and Drug Inspector exam

Types of Processes: The preparation of parenteral products may be categorized as small-scale dispensing, usually one unit at a time, or large-scale manufacturing in which hundreds of thousands of units may constitute one lot of product. In the pursuit of cGMP, consideration should be given to:

  • Ensuring that the personnel responsible for assigned duties are capable and qualified to perform them.
  • Ensuring that ingredients used in compounding the product have the required identity, quality, and purity.
  • Validating critical processes to be sure the equipment used and the processes followed ensure that the finished product hase the qualities expected.
  • Maintaining a production environment suitable for performing the critical processes required, addressing such matters as orderliness, cleanliness, asepsis, and avoidance of cross contamination.
  • Confirming, through adequate quality-control procedures, that the finished products have the required potency, purity, and quality.
  • Establishing, through appropriate stability evaluation, that the drug products retain their intended potency, purity, and quality, until the established expiration date.
  • Ensuring that processes are always carried out in accord with established, written procedures.
  • Providing adequate conditions and procedures for the prevention of mix-ups.
  • Establishing adequate procedures, with supporting documentation, for investigating and correcting failures or problems in production or quality control.
  • Providing adequate separation of quality-control responsibilities from those of production to ensure independent decision making.

In concert with the pursuit of cGMPs, the pharmaceutical industry has shown initiative and innovation in the extensive technological development and improvement in quality, safety, and effectiveness of parenteral dosage forms in recent years. Examples include developments in:

  • modular facility design and construction—smaller rooms, easier to clean, sanitize, and maintain;
  • application of disposable technologies for compounding, mixing, and filling—reduce potential for cross contamination;
  • closure cleaning, siliconization (if applicable), and sterilization—all-in-one systems for rubber closures;
  • sterilization technologies—well-defined sterilization validation principles, multiple approaches to sterilization cycles;
  • filling technologies—greater speed, precision, and handling of viscous solutions;
  • aseptic processing technology, including barrier isolator technology and restricted access barrier systems;
  • freeze-drying technologies–automated loading and unloading, advances in process monitoring;
  • control of particulate matter—greater diligence in cleaning methodologies, in-coming inspections, more experience with sources, causes, and minimization of particulate matter in facilities, on equipment and packaging, and personnel practices; and
  • Automation—weight checking, inspection technologies, labeling and finishing operations.

General manufacturing Process: The preparation of a parenteral product may encompass four general areas:

  • Procurement and accumulation of all components in a warehouse area, until released to manufacturing;
  • Processing the dosage form in appropriately designed and operated facilities;
  • Packaging and labeling in a quarantine area, to ensure integrity and completion of the product; and
  • Controlling the quality of the product throughout the process.

Procurement encompasses selecting and testing according to specifications of the raw-material ingredients and the containers and closures for the primary and secondary packages. Microbiological purity, in the form of bioburden and endotoxin levels, has become standard requirements for raw materials.

Processing includes cleaning containers and equipment to validated specifications, compounding the solution (or other dosage form), filtering the solution, sanitizing or sterilizing the containers and equipment, filling measured quantities of product into the sterile containers, stoppering (either completely or partially for products to be freeze-dried), freeze-drying, terminal sterilization (if possible), and final sealing of the final primary container.

Packaging normally consists of the labeling and cartoning of filled and sealed primary containers. Control of quality begins with the incoming supplies, being sure that specifications are met. Careful control of labels is vitally important, as errors in labeling can be dangerous for the consumer. Each step of the process involves checks and tests to ensure the required specifications at the respective step are being met. Labeling and final packaging operations are becoming more automated.

The quality control unit is responsible for reviewing the batch history and performing the release testing required to clear the product for shipment to users. A common FDA citation for potential violation of cGMP is the lack of oversight by the quality control unit in batch testing and review and approval of results.

Components: Components of parenteral products include the active ingredient, formulation additives, vehicle(s), and primary container and closure.

Water for injection (WFI):

Preparation – Water for Injection can be prepared by distillation or by membrane technologies (i.e., reverse osmosis or ultrafiltration). The EP (European Pharmacopeia) only permits distillation as the process for producing WFI. The USP and JP (Japanese Pharmacopeia) allow all these technologies to be applied.

The specific construction features of a still and the process specifications have a marked effect on the quality of distillate obtained from a still. Several factors must be considered in selecting a still to produce WFI:

  • The quality of the feed water will affect the quality of the distillate. For example, chlorine in water, especially, can cause or exacerbate corrosion in distillation units, and silica causes scaling within. Controlling the quality of the feed water is essential for meeting the required specifications for the distillate.
  • The size of the evaporator will affect the efficiency. It should be large enough to provide a low vapor velocity, thus, reducing the entrainment of the distilland either as a film on vapor bubbles or as separate droplets.
  • The baffles (condensing surfaces) determine the effectiveness of refluxing. They should be designed for efficient removal of the entrainment at optimal vapor velocity, collecting and returning the heavier droplets contaminated with the distilland.
  • Redissolving volatile impurities in the distillate reduces its purity. Therefore, they should be separated efficiently from the hot water vapor and eliminated by aspirating them to the drain or venting them to the atmosphere.
  • Contamination of the vapor and distillate from the metal parts of the still can occur. Present standards for high-purity stills are that all parts contacted by the vapor or distillate should be constructed of metal coated with pure tin, 304 or 316 stainless-steel, or chemically resistant glass.

There are two basic types of WFI distillation units—the vapor compression still and the multiple effect still.

Compression Distillation – The vapor-compression still, primarily designed for the production of large volumes of high-purity distillate with low consumption of energy and water. To start, the feed water is heated from an external source in the evaporator to boiling. The vapor produced in the tubes is separated from the entrained distilland in the separator and conveyed to a compressor that compresses the vapor and raises its temperature to approximately 107°C. It then flows to the steam chest, where it condenses on the outer surfaces of the tubes containing the distilland; the vapor is, thus, condensed and drawn off as a distillate, while giving up its heat to bring the distilland in the tubes to the boiling point. Vapor-compression stills are available in capacities from 50 to 2800 gal/hr.

Figure 1 – Vapor compressor still

Multiple Effect Still – The multiple-effect still is also designed to conserve energy and water usage. In principle, it is simply a series of single-effect stills or columns running at differing pressures where phase changes of water take place. A series of up to seven effects may be used, with the first effect operated at the highest pressure and the last effect at atmospheric pressure. Steam from an external source is used in the first effect to generate steam under pressure from feed water; it is used as the power source to drive the second effect. The steam used to drive the second effect condenses as it gives up its heat of vaporization and forms a distillate. This process continues until the last effect, when the steam is at atmospheric pressure and must be condensed in a heat exchanger. The capacity of a multiple-effect still can be increased by adding effects. The quantity of the distillate will also be affected  by the inlet steam pressure; thus, a 600-gal/hr unit designed to operate at 115 psig steam pressure could be run at approximately 55 psig and would deliver about 400 gal/hr. These stills have no moving parts and operate quietly. They are available in capacities from about 50 to 7000 gal/hr.

Figure 2 – Multiple effect still

Reverse Osmosis (RO) – As the name suggests, the natural process of selective permeation of molecules through a semipermeable membrane separating two aqueous solutions of different concentrations is reversed. Pressure, usually between 200 and 400 psig, is applied to overcome osmotic pressure and force pure water to permeate through the membrane. Membranes, usually composed of cellulose esters or polyamides, are selected to provide an efficient rejection of contaminant molecules in raw water. The molecules most difficult to remove are small inorganic molecules, such as sodium chloride. Passage through two membranes in series is sometimes used to increase the efficiency of removal of these small molecules and decrease the risk of structural failure of a membrane to remove other contaminants, such as bacteria and pyrogens. Several WFI installations utilize both RO and distillation systems for generation of the highest quality water. Since feedwater to distillation units can be heavily contaminated and, thus, affect the operation of the still, water is first run through RO units to eliminate contaminants.

Storage and Distribution – The rate of production of WFI is not sufficient to meet processing demands; therefore, it is collected in a holding tank for subsequent use. In large operations, the holding tanks may have a capacity of several thousand gallons and be a part of a continuously operating system. In such instances, the USP requires that the WFI be held at a temperature too high for microbial growth, normally a constant 80°C. The USP also permits the WFI to be stored at room temperature but for a maximum of 24 hours. Under such conditions, the WFI is collected as a batch for a particular use with any unused water discarded within 24 hours. Such a system requires frequent sanitization to minimize the risk of viable microorganisms being present. The stainless-steel storage tanks in such systems are usually connected to a welded stainlesssteel distribution loop, supplying the various use sites with a continuously circulating water supply. The tank is provided with a hydrophobic membrane vent filter capable of excluding bacteria and nonviable particulate matter. Such a vent filter is necessary to permit changes in pressure during filling and emptying. The construction material for the tank and connecting lines is usually electropolished 316L stainless steel with welded pipe. The tanks also may be lined with glass or a coating of pure tin. Such systems are very carefully designed and constructed and often constitute the most costly installation within the plant. When the water cannot be used at 80°C, heat exchangers must be installed to reduce the temperature at the point of use. Bacterial retentive filters should not be installed in such systems, due to the risk of bacterial buildup on the filters and the consequent release of pyrogenic substances.

Purity – Although certain purity requirements have been alluded to, the USP and EP monographs provide the official standards of purity for WFI and Sterile Water for Injection (SWFI). The only physical/chemical tests remaining are the new total organic carbon (TOC), with a limit of 500 ppb (0.5 mg/L), and conductivity, with a limit of 1.3 μS/cm at 25°C or 1.1 μS/cm at 20°C. The former is an instrumental method capable of detecting all organic carbon present, and the latter is a three-tiered instrumental test measuring the conductivity contributed by ionized particles (in microSiemens or micromhos) relative to pH. Since conductivity is integrally related to pH, the pH requirement of 5 to 7 in previous revisions has been eliminated. The TOC and conductivity specifications are now considered adequate minimal predictors of the chemical/physical purity of WFI. However, the wet chemistry tests are still used when WFI is packaged for commercial distribution and for SWFI. Biological requirements continue to be, for WFI, not more than 10 colony-forming units (CFUs)/100 mL and less than 0.25 USP endotoxin units/mL. The SWFI requirements differ in that, since it is a final product, it must pass the USP Sterility Test. WFI and SWFI may not contain added substances. Bacteriostatic Water for Injection (BWFI) may contain one or more suitable antimicrobial agents in containers of 30 mL or less. This restriction is designed to prevent the administration of a large quantity of a bacteriostatic agent that would probably be toxic in the accumulated amount of a large volume of solution, even though the concentration was low.

Multiple Choice Questions:

1.The preparation of parenteral products may be categorized as

a)small-scale

b)large-scale

c)both of these

d)none of these

2.In small-scale dispensing

a)usually one unit at a time manufacturing is done

b)hundreds of thousands of units may constitute one lot of product

c)both of these

d)none of these

3.In the pursuit of cGMP, consideration should be given to

a)Ensuring that the personnel responsible for assigned duties are capable and qualified to perform them

b)Ensuring that ingredients used in compounding the product have the required identity, quality, and purity

c)Validating critical processes to be sure the equipment used and the processes followed ensure that the finished product hase the qualities expected

d)All of these

4.In the pursuit of cGMP, consideration should be given to confirming, through adequate quality-control procedures, that the finished products have the required

a)potency

b)purity

c)quality

d)all of these

5.Modular facility design and construction include

a)smaller rooms

b)larger rooms

c)both of these

d)none of these

6.In concert with the pursuit of cGMPs, the pharmaceutical industries include

a)filling technologies

b)freeze-drying technologies

c)Automation

d)all of these

7.Automation includes

a)weight checking

b)inspection technologies

c)labeling and finishing operations

d)all of these

8.The preparation of a parenteral product may encompass ____ general areas

a)one

b)two

c)three

d)four

9.The preparation of a parenteral product may encompass which of the following general areas?

a)Procurement

b)Processing

c)Controlling the quality

d)All of these

10.Which of the following encompasses selecting and testing according to specifications of the raw-material ingredients and the containers and closures for the primary and secondary packages?

a)Procurement

b)Processing

c)Controlling the quality

d)Packaging

11.Which of the following includes cleaning containers and equipment to validated specifications, compounding the solution (or other dosage form), filtering the solution, sanitizing or sterilizing the containers and equipment, filling measured quantities of product into the sterile containers, stoppering (either completely or partially for products to be freeze-dried), freeze-drying, terminal sterilization (if possible), and final sealing of the final primary container?

a)Procurement

b)Processing

c)Controlling the quality

d)Packaging

12.Which of the following normally consists of the labeling and cartoning of filled and sealed primary containers?

a)Procurement

b)Processing

c)Controlling the quality

d)Packaging

13.Which of the following is responsible for reviewing the batch history and performing the release testing required to clear the product for shipment to users?

a)Procurement

b)Processing

c)Controlling the quality

d)Packaging

14.Components of parenteral products include

a)formulation additives

b)vehicle(s)

c)primary container and closure

d)all of these

15. Which of the following is/are basic types of WFI distillation units?

a)the vapor compression still

b)the multiple effect still

c)RO

d)a and b

Solutions:

  1. c)both of these
  2. a)usually one unit at a time manufacturing is done
  3. d)All of these
  4. d)all of these
  5. a)smaller rooms
  6. d)all of these
  7. d)all of these
  8. d)four
  9. d)All of these
  10. a)Procurement
  11. b)Processing
  12. d)Packaging
  13. c)Controlling the quality
  14. d)all of these
  15. d)a and b

References:

  1. Remington Essential of Pharmaceutics, 1st edition 2013, page no. 499-504.

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